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Enzalutamide, MDV-3100

MDV3100 is an orally bioavailable, organic, non-steroidal small molecule targeting the androgen receptor (AR) with potential antineoplastic activity. MDV3100 (Enzalutamide) blocks androgens from binding to the androgen receptor and prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex. It also induces tumour cell apoptosis, and has no agonist activity. Early preclinical studies also suggest that MDV3100 inhibits breast cancer cell growth.

Processes for the preparation of enzalutamide are described in U.S. Publication Nos. 2007/0004753 and 2007/0254933 and PCT Publication Nos. WO 2007/127010, WO 2006/124118, and WO 2011/106570.

PCT Publication No. WO 2011/106570 discloses that the processes described in U.S. Publication Nos. 2007/0004753 and 2007/0254933 result in a 25% yield of enzalutamide in the final step, which accounts for a 15% overall yield. PCT Publication No. WO 2011/106570 further discloses that the known processes for preparing enzalutamide involve the use of extremely toxic reagents, for example, acetone cyanohydrin.

Acetone cyanohydrin is toxic and therefore its use as a reagent should be avoided for industrial production of a pharmaceutical ingredient. Thus, there is a need in the art to develop a process for the preparation of enzalutamide that avoids the use of acetone cyanohydrin as a reagent

Example 6: Process for the preparation of Enzalutamide (Formula I)

Ethyl N-[3-fluoro-4-(methylcarbamoyl)-phenyl]-2-methylalaninate (Formula IV; 0.2 g) and 4-isothiocyanato 2-(triflouromethyl)-benzonitrile (Formula V; 0.33 g) were added to dimethyl sulfoxide (0.2 mL) and isopropyl acetate (0.4 mL) and heated to 90°C to 95°C. The reaction mixture was cooled to 70°C followed by the addition of methanol (0.4 mL). The reaction mixture was stirred for 2 hours. Isopropyl acetate (4 mL) was added to the reaction mixture followed by washing with water (4 mL). The organic layer was concentrated at 35°C under vacuum to obtain an oily residue which was further purified using silica gel column to obtain the title compound.

Yield: 0.2 g

…………………………

PAPER

J Med Chem 2010, 53(7): 2779

http://pubs.acs.org/doi/full/10.1021/jm901488g
A structure−activity relationship study was carried out on a series of thiohydantoins and their analogues 14 which led to the discovery of 92 (MDV3100) as the clinical candidate for the treatment of hormone refractory prostate cancer.

Dolutegravir key intermediate which is from Maltol. Another two intermediates those are Chiral amine & Difluoro i prepared successfully. Now we want to pepare key intermediate which is from Maltol. completed 3 steps. in 4th step we need to use CO gas with palladium acetate (replace Bromo) at ortho position to get Ester compound.
I want without CO how to prepare? pl suggest
We tried NACN, KtertButoxide like… no reactinon

Dr Anthony, Day in and day out you dish out excellent stuff and nowadays some spectroscopy also, How do you get time, may Allah give you all the strenght and will to continue helping all and specially Pakistan chemists

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international,
etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules
and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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